The primary objective of this project is to develop an effective, peptide-based nicotine vaccine for use in humans capable of inducing a robust, nicotine-specific antibody (Ab) response with little or no inflammatory side effects. This will be accomplished by vaccine designs in which conformationally biased, response-selective agonists of C5a (YSFKPMPLaR and YSFKDMP(MeL)a) are used as molecular adjuvants and a nicotine hapten is used as the target antigen (Ag). The ability of such molecular adjuvant-containing vaccines to induce an anti-nicotine immune response will be assessed by two general methods. The first is to characterize the molecular and cellular mechanisms by which the molecular adjuvants engage C5a receptor (C5aR)-bearing antigen presenting cells (APC) to enhance the APCs' ability to process and present the nicotine Ag. The second is to vaccinate rats with molecular adjuvant-containing nicotine vaccines in the absence of added adjuvant and demonstrate the presence of nicotine-specific Abs in immune sera/tissues and an attenuation of nicotine-induced behavioral effects in two well-established rat models of nicotine dependence. Validation of these peptide-based, molecular adjuvant-containing nicotine vaccines represents the first step toward realization of the broad objective sought by this project, which is to use vaccination to nicotine with such vaccines as a standard therapeutic regimen for smoking cessation and maintenance of long term compliance. The first steps toward this broad objective will be taken with the following specific aims: 1) To characterize the cellular and molecular mechanisms by which the molecular adjuvants YSFKPMPLaR and YSFKDMP(MeL)aR engage C5aR-bearing human APCs such that these cells are activated and their Ag processing/presenting capacity is enhanced. 2) To test YSFKPMPLaR- and YSFKDMP(MeL)aR-containing nicotine vaccines for their ability to induce anti-nicotine immune responses in rats without the use of added adjuvants, and 3) To test whether vaccination with YSFKPMPLaR- and YSFKDMP(MeL)aR-containing vaccines attenuates the behavioral effects of nicotine in well-characterized rat models of nicotine dependence.